A new review of clinical trials suggests that psychedelics like psilocybin are effective for treating depression but offer no advantage over traditional antidepressants. Researchers accounted for the challenge of blinding in psychedelic studies, where participants can often tell if they received the drug. The findings indicate similar outcomes when compared to unblinded antidepressant trials.
Researchers led by Balázs Szigeti at the University of California, San Francisco (UCSF), analyzed 24 trials to compare psychedelic-assisted therapy (PAT) with traditional antidepressants for depression treatment. Eight trials examined PAT, combining psychotherapy with drugs such as psilocybin, LSD, and DMT. The other 16 were open-label trials of antidepressants, where both participants and researchers knew the treatment given, forgoing blinding typically used to counter placebo effects in drug studies. In psychedelic trials, participants can often detect the active drug due to its hallucinogenic effects, potentially inflating benefits through expectation. The review found antidepressants outperformed PAT by just 0.3 points on a 52-point depression-rating scale—a difference neither statistically nor clinically significant. Previously, psychedelics showed a 7.3-point improvement over placebo, compared to 2.4 points for antidepressants. Szigeti noted, “Our results do not disprove the exciting results about psychedelic treatments... it is just that they are not more effective than open-label traditional antidepressants, which feels underwhelming given the attention [on psychedelics].” Matthew Johnson at Johns Hopkins University called the approach “intriguing,” criticizing some researchers for lacking a “principled approach.” Rayyan Zafar at Imperial College London urged direct head-to-head comparisons, citing one psilocybin versus escitalopram trial that found no significant difference. Robin Carhart-Harris, also at UCSF, critiqued the method as comparing “apples with oranges” due to varying trial designs. The study appears in JAMA Psychiatry (DOI: 10.1001/jamapsychiatry.2025.4809).
